1. Field of the Invention
The present invention is related to a process for the manufacturing of new multiple unit carriers and release controlling systems for bioactive materials as well as the manufacturing of a new additive to be used in the formation of tablets and especially in direct compression and to obtain multiple unit preparations in the form of compressed and disintegrating tablets.
2. Background of the Invention
This invention relates to the administration or dispersion of bioactive materials in the form of small discrete particles, often referred to as multiple unit (MU) preparations or systems. It is well known that MU systems offer several advantages such as good dosing and handling properties as well as excellent possibilities to obtain a controlled release of the active ingredient, or ingredients.
The control of the release rate, or other release properties, can be achieved in a number of different ways such as using hydrophobic and or hydrophilic materials in which the bioactive material is embedded and released by a diffusion or erosion process as well as coating particles (crystals, beads, pellets etc.) with a release controlling barrier.
The barrier may be designed e.g. to control the release rate by diffusion- or osmotic processes or to delay the release by a controlled disintegration of the barrier, which may be designed to be affected by environmental conditions such as humidity, pH, microorganisms or enzymes.
The above mentioned release controlling systems have been of special importance within the pharmaceutical field during the last decades. Apart from the possibilities to control the delivery of drugs to humans or creatures, and thus to obtain therapeutical advantages for a large number of drugs, several advantages with MU preparations compared to single unit preparations have been described in the literature.
It is, for example, possible to obtain a more reproducible emptying of small units (e.g. less than 1-2 mm, c.f. Bogentoft C et al, Influence of food on the absorption of acetylsalicylic acid from enteric coated dosage forms, Europ. J. Clin. Pharmacol. (1978), 14, 351-355) and thus a dispersion over a large area of the gastrointestinal canal. This may promote the absorption process, causing reduced variability, as well as reduced local irritation in the oesophagus or other parts of the gastrointestinal tract.
A large number of processes have been developed to produce the MU cores. The cores may include release retarding components, be intended for further processing such as coating with suitable materials or may simply act as a carrier for the active material. The processes includes for example controlled crystallization and mechanical formation of spherical particles from mixtures of active substances and hydroplastic additives as well as spray drying and spray chilling processes. There are numerous ways to form spherical small particles by mechanical processes, e.g. by using coating drums, pans and extrusion/spheronization and fluid bed equipment (Pharmaceutical Pelletization Technology, Ed. I Ghebre Sellassie, Marcel Dekker, Inc New York 1989).
It is, in general, very critical to get particles of a well defined size, form and surface area (Ragnarsson and Johansson, ref. Drug Dev. Ind. Pharm. 14, 2285 (1988) in order to obtain good handling properties, good dose uniformity or accurate control of the release properties. To fulfill these requirements, the production processes are in general complex including several steps and often finished by e.g. a sieving process to obtain uniform particles. A manufacturing process including many steps will be time consuming and expensive but may also pose environmental hazards when handling toxic or irritating substances. Of special importance is the loss of active material in the different production steps and, especially, when sieving materials in order to obtain the required particle size fraction.
The optimal solution would be to produce spherical inert particles of the required particle size and size distribution that can be loaded with the bioactive material, e.g. by sorption into a porous structure, and that optionally may control the release of the bioactive material. It would thus be possible to reduce the number of production steps and the production costs, to minimize losses of active material during manufacturing and to reduce environmental problems.
It has previously been described (U.S. Pat. No. 3,297,806) that agglomerated cellulose produced by spray drying can be used for loading of substances in order to obtain a chemical stabilization of the substances especially from oxidation. The described procedure does, however, give cellulose agglomerates with a limited sorbing capacity (less than 1.5 times of water of the weight of the cellulose agglomerates according to the examples). The described material is identical with commercial microcrystalline cellulose for tabletting (e.g. Avicel and Dynacel). Furthermore, no mechanical treatment is performed prior to loading of the substance to be stabilized. Fractionation in order to obtain defined particle sizes is, in this case, performed on the loaded agglomerates which lead to reject fractions of undesirable particle sizes containing the loaded substance which in many cases is very costly.
It has also been described that agglomerates can be formed from cellulose derivatives (G. B. Patent 1 575 700) to be used for immobilization of e.g. enzymes through ionic or chemical covalent bonding. However, the carrier system is not built up from pure cellulose and the immobilization of the molecules is not built basically on physical entrapment.
An abstract from Japanese patent application JP 88101288 discloses porous cellulose particles in a crystalline form with fine pores, a porosity higher than 20% and more than 90% over 350 mesh. (=40 micron) which are used as additives for tabletting of drugs and as a carrier. The process disclosed cannot give particles which are regular and which have a high sorbing capacity.
Pharmaceutical products of the MU type are often dispersed in hard gelatin capsules. They may also be dispersed in compressed disintegrating tablets. These types of tablets offer some advantages compared to capsules or sachets such as being an elegant dosage form and giving units that can be divided into two or more dose units or disintegrated in water to make the drug easier to swallow.
The production of tablets based on barrier coated MU-cores is however associated with some special problems. To protect the coating layer from being disrupted during compression, it is in general necessary to add materials with good bonding properties that will aid in the formation of tablets as well as to protect the coating layer. The material should preferably have suitable plastic properties, i.e., be easily deformed and form strong compacts at low pressure. Such typical material is microcrystalline cellulose, available on the market under the trade names of, for example, Avicel (FMC Corp.), Emcocel (Finn Sugar, Finland) and Dynacel (Cellupharm AB, Sweden). Although these materials have outstanding compaction properties, as discussed above, they are not ideal as additives for compressed MU preparations. The main drawback is that they differ considerably in form, size and size distribution from MU cores. As the MU cores in general are spherical particles in the particle size range of 0.5-1.5 mm, they will form a free flowing material that when mixed with commercially available microcrystalline cellulose qualities will tend to give severe segregation during handling and tabletting and thus poor content uniformity.
The optimal solution would be to use materials of exactly the same size and size distribution as the MU cores but with very good tabletting properties. It is widely recognized that it is extremely difficult to obtain such materials by granulation methods or other conventional pharmaceutical processes, based on microcrystalline cellulose or other pharmaceutically acceptable substances. Materials of the preferred type, i.e., with a well defined particle form and adjustable and narrow particle size as well as excellent compaction properties, would also be of very large general interest in the manufacturing of tablets and especially in direct compression.